Gleevec

SIDE EFFECTS

Because clinical trials are conducted under widely
varying conditions, the adverse reaction rates observed cannot be directly
compared to rates on other clinical trials and may not reflect the rates
observed in clinical practice.

Chronic Myeloid Leukemia

The majority of Gleevec-treated patients experienced
adverse reactions at some time, most adverse reactions were of mild-to-moderate
grade. Gleevec was discontinued due to drug-related adverse reactions in 2.4%
of patients receiving Gleevec in the randomized trial of newly diagnosed
patients with Ph+ CML in chronic phase comparing Gleevec versus INF+Ara-C, and
in 12.5% of patients receiving Gleevec in the randomized trial of newly
diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and
nilotinib. Gleevec was discontinued due to drug-related adverse reactions in 4%
of patients in chronic phase after failure of interferon-alpha therapy, in 4%
of pa tients in accelerated phase and in 5% of patients in blast crisis.

The most frequently reported drug-related adverse
reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain,
diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for
other CML patients). Edema was most frequently periorbital or in lower limbs
and was managed with diuretics, other supportive measures, or by reducing the
dose of Gleevec [seeDOSAGE AND ADMINISTRATION]. The frequency of severe
superficial edema was 1.5%-6%.

A variety of adverse reactions represent local or general
fluid retention including pleural effusion, ascites, pulmonary edema and rapid
weight gain with or without superficial edema. These reactions appear to be
dose related, were more common in the blast crisis and accelerated phase
studies (where the dose was 600 mg/day), and are more common in the elderly.
These reactions were usually managed by interrupting Gleevec treatment and
using diuretics or other appropriate supportive care measures. A few of these
reactions may be serious or life threatening, and one patient with blast crisis
died with pleural effusion, congestive heart failure, and renal failure.

Adverse reactions, regardless of relationship to study
drug, that were reported in at least 10% of the Gleevec treated patients are
shown in Tables 2, 3, and 4.

Hematologic and Biochemistry
Laboratory Abnormalities

Cytopenias, and particularly
neutropenia and thrombocytopenia, were a consistent finding in all studies,
with a higher frequency at doses ≥ 750
mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly
diagnosed CML, cytopenias were less frequent than in the other CML patients
(see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and
thrombocytopenia was between 2- and 3-fold higher in blast crisis and
accelerated phase compared to chronic phase (see Tables 4 and 5). The median
duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3
weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed
with either a reduction of the dose or an interruption of treatment with
Gleevec, but in rare cases require permanent discontinuation of treatment.

Hepatotoxicity

Severe elevation of
transaminases or bilirubin occurred in approximately 5% of CML patients (see
Tables 6 and 7) and were usually managed with dose reduction or interruption
(the median duration of these episodes was approximately 1 week). Treatment was
discontinued permanently because of liver laboratory abnormalities in less than
1.0% of CML patients. One patient, who was taking acetaminophen regularly for
fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4
SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT
(AST) elevations were observed in 4.8% of patients. Bilirubin elevation was
observed in 2.7% of patients.

Adverse Reactions In Pediatric
Population

Single Agent Therapy

The overall safety profile of
pediatric patients treated with Gleevec in 93 children studied was similar to
that found in studies with adult patients, except that musculoskeletal pain was
less frequent (20.5%) and peripheral edema was not reported. Nausea and
vomiting were the most commonly reported individual adverse reactions with an
incidence similar to that seen in adult patients. Although most patients
experienced adverse reactions at some time during the study, the incidence of
Grade 3/4 adverse reactions was low.

In Combination With Multi-Agent Chemotherapy

Pediatric and young adult patients with very high risk
ALL, defined as those with an expected 5 year event-free survival (EFS) less
than 45%, were enrolled after induction therapy on a multicenter,
non-randomized cooperative group pilot protocol. The study population included
patients with a median age of 10 years (1 to 21 years), 61% of whom were male,
75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with
Ph+ ALL (n=92) were assigned to receive Gleevec and treated in 5 successive cohorts.
Gleevec exposure was systematically increased in successive cohorts by earlier
introduction and more prolonged duration.

The safety of Gleevec given in combination with intensive
chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse
events, neutropenia ( < 750/mcL) and thrombocytopenia ( < 75,000/mcL) in the
92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the
trial who did not receive Gleevec. The safety was also evaluated comparing the
incidence of adverse events in cycles of therapy administered with or without
Gleevec. The protocol included up to 18 cycles of therapy. Patients were
exposed to a cumulative total of 1425 cycles of therapy, 778 with Gleevec and
647 without Gleevec. The adverse events that were reported with a 5% or greater
incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater
incidence in cycles of therapy that included Gleevec are presented in Table 8.

* Defined as the frequency of
AEs per patient per treatment cycles that included Gleevec (includes patients
with Ph+ ALL that received cycles with Gleevec
** Defined as the frequency of AEs per patient per treatment cycles that did
not include Gleevec (includes patients with Ph+ ALL that received cycles
without Gleevec as well as all patients with Ph- ALL who did not receive
Gleevec in any treatment cycle)

Adverse Reactions In Other
Subpopulations

In older patients ( ≥ 65 years old), with the exception of edema, where
it was more frequent, there was no evidence of an increase in the incidence or
severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade ½
superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No
differences were seen that were related to race but the subsets were too small
for proper evaluation.

Acute Lymphoblastic Leukemia

The adverse reactions were
similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related
adverse reactions reported in the Ph+ ALL studies were mild nausea and
vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily
manageable. Superficial edema was a common finding in all studies and were
described primarily as periorbital or lower limb edemas. These edemas were
rarely severe and may be managed with diuretics, other supportive measures, or
in some patients by reducing the dose of Gleevec.

Myelodysplastic/Myeloproliferative
Diseases

Adverse reactions, regardless
of relationship to study drug, that were reported in at least 10% of the
patients treated with Gleevec for MDS/MPD in the phase 2 study, are shown in Table
9.

Hypereosinophilic Syndrome And Chronic
Eosinophilic Leukemia

The safety profile in the
HES/CEL patient population does not appear to be different from the safety
profile of Gleevec observed in other hematologic malignancy populations, such
as Ph+ CML. All patients experienced at least one adverse reaction, the most
common being gastrointestinal, cutaneous and musculoskeletal disorders.
Hematological abnormalities were also frequent, with instances of CTC Grade 3
leukopenia, neutropenia, lymphopenia, and anemia.

Dermatofibrosarcoma Protuberans

Adverse reactions, regardless
of relationship to study drug, that were reported in at least 10% of the 12
patients treated with Gleevec for DFSP in the phase 2 study are shown in Table
10.

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant
Metastatic GIST

In the Phase 3 trials, the
majority of Gleevec-treated patients experienced adverse reactions at some
time. The most frequently reported adverse reactions were edema, fatigue,
nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and
anorexia. Drug was discontinued for adverse reactions in a total of 89 patients
(5.4%). Superficial edema, most frequently periorbital or lower extremity edema
was managed with diuretics, other supportive measures, or by reducing the dose
of Gleevec [see DOSAGE AND ADMINISTRATION]. Severe (CTC Grade 3/4) edema
was observed in 182 patients (11.1%).

Adverse reactions, regardless
of relationship to study drug, that were reported in at least 10% of the
patients treated with Gleevec are shown in Table 12.

Overall the incidence of all grades of adverse reactions
and the incidence of severe adverse reactions (CTC Grade 3 and above) were
similar between the two treatment arms except for edema, which was reported
more frequently in the 800 mg group.

Table 12 : Number (%) of
Patients with Adverse Reactions Regardless of Relationship to Study Drug where
Frequency is ≥ 10% in any One Group (Full Analysis Set) in the Phase 3
Unresectable and/or Malignant Metastatic GIST Clinical Trials

Reported or Specified Term

Imatinib 400 mg
N=818

Imatinib 800 mg
N=822

All Grades %

Grades 3/4/5 %

All Grades %

Grades 3/4/5 %

Edema

76.7

9.0

86.1

13.1

Fatigue/lethargy, malaise, asthenia

69.3

11.7

74.9

12.2

Nausea

58.1

9.0

64.5

7.8

Abdominal pain/cramping

57.2

13.8

55.2

11.8

Diarrhea

56.2

8.1

58.2

8.6

Rash/desquamation

38.1

7.6

49.8

8.9

Vomiting

37.4

9.2

40.6

7.5

Myalgia

32.2

5.6

30.2

3.8

Anemia

32.0

4.9

34.8

6.4

Anorexia

31.1

6.6

35.8

4.7

Other GI toxicity

25.2

8.1

28.1

6.6

Headache

22.0

5.7

19.7

3.6

Other pain (excluding tumor related pain)

20.4

5.9

20.8

5.0

Other dermatology/skin toxicity

17.6

5.9

20.1

5.7

Leukopenia

17.0

0.7

19.6

1.6

Other constitutional symptoms

16.7

6.4

15.2

4.4

Cough

16.1

4.5

14.5

3.2

Infection (without neutropenia)

15.5

6.6

16.5

5.6

Pruritus

15.4

5.4

18.9

4.3

Other neurological toxicity

15.0

6.4

15.2

4.9

Constipation

14.8

5.1

14.4

4.1

Other renal/genitourinary toxicity

14.2

6.5

13.6

5.2

Arthralgia (joint pain)

13.6

4.8

12.3

3.0

Dyspnea (shortness of breath)

13.6

6.8

14.2

5.6

Fever in absence of neutropenia (ANC < 1.0 x 109/L)

13.2

4.9

12.9

3.4

Sweating

12.7

4.6

8.5

2.8

Other hemorrhage

12.3

6.7

13.3

6.1

Weight gain

12.0

1.0

10.6

0.6

Alopecia

11.9

4.3

14.8

3.2

Dyspepsia/heartburn

11.5

0.6

10.9

0.5

Neutropenia/ granulocytopenia

11.5

3.1

16.1

4.1

Rigors/chills

11.0

4.6

10.2

3.0

Dizziness/lightheadedness

11.0

4.8

10.0

2.8

Creatinine increase

10.8

0.4

10.1

0.6

Flatulence

10.0

0.2

10.1

0.1

Stomatitis/pharyngitis (oral/pharyngeal mucositis)

9.2

5.4

10.0

4.3

Lymphopenia

6.0

0.7

10.1

1.9

Clinically relevant or severe
abnormalities of routine hematologic or biochemistry laboratory values were not
reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory
values reported in the Phase 2 GIST trial are presented in Table 13.

Adjuvant Treatment of GIST

In Study 1, the majority of
both Gleevec and placebo treated patients experienced at least one adverse
reaction at some time. The most frequently reported adverse reactions were
similar to those reported in other clinical studies in other patient
populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin,
rash, vomiting, and abdominal pain. No new adverse reactions were reported in
the adjuvant GIST treatment setting that had not been previously reported in
other patient populations including patients with unresectable and/or malignant
metastatic GIST. Drug was discontinued for adverse reactions in 57 patients
(17%) and 11 patients (3%) of the Gleevec and placebo treated patients
respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal
distention and diarrhea), fatigue, low hemoglobin, and rash were the most
frequently reported adverse reactions at the time of discontinuation.

In Study 2, discontinuation of
therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients
(14%) of the Gleevec 12-month and 36-month treatment arms, respectively. As in
previous trials the most common adverse reactions were diarrhea, fatigue,
nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Adverse reactions, regardless
of relationship to study drug, that were reported in at least 5% of the
patients treated with Gleevec are shown in Table 14 (Study 1) and Table 15 (Study
2). There were no deaths attributable to Gleevec treatment in either trial.

1 All adverse reactions occurring in ≥ 5% of patients are
listed regardless of suspected relationship to treatment. A patient with
multiple occurrences of an adverse reaction is counted only once in the adverse
reaction category.

1 All adverse reactions occurring in ≥ 5% of patients are
listed regardless of suspected relationship to treatment. A patient with
multiple occurrences of an adverse reaction is counted only once in the adverse
reaction category.

Additional Data From Multiple
Clinical Trials

The following adverse reactions
have been reported during clinical trials of Gleevec.

Postmarketing Experience

The following additional adverse reactions have been
identified during post approval use of Gleevec. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

DRUG INTERACTIONS

Agents Inducing CYP3A Metabolism

Pretreatment of healthy volunteers with multiple doses of
rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose
clearance by 3.8-fold, which significantly (p < 0.05) decreased mean Cmax and
AUC.

Concomitant administration of Gleevec and St. John's Wort
led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme
induction potential in patients when rifampin or other CYP3A4 inducers are
indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to
patients receiving concomitant strong CYP3A4 inducers [see DOSAGE AND
ADMINISTRATION].

Agents Inhibiting CYP3A Metabolism

There was a significant increase in exposure to imatinib
(mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects
when Gleevec was coadministered with a single dose of ketoconazole (a CYP3A4
inhibitor). Caution is recommended when administering Gleevec with strong
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, and voriconazole). Grapefruit juice may also increase plasma
concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome
P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib
concentrations.

Interactions With Drugs Metabolized By CYP3A4

Gleevec increases the mean Cmax and AUC of simvastatin
(CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of
the CYP3A4 by Gleevec. Particular caution is recommended when administering
Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g.,
alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus or tacrolimus).

Because warfarin is metabolized by CYP2C9 and CYP3A4,
patients who require anticoagulation should receive low-molecular weight or
standard heparin instead of warfarin.

Interactions With Drugs Metabolized By CYP2D6

Gleevec increased the mean Cmax and AUC of metoprolol by
approximately 23% suggesting that Gleevec has a weak inhibitory effect on
CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution
is recommended when administering Gleevec with CYP2D6 substrates that have a
narrow therapeutic window.

Interaction With Acetaminophen

In vitro, Gleevec inhibits the acetaminophen
O-glucuronidate pathway (Ki 58.5 μM). Coadministration of Gleevec (400
mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in
patients with CML did not result in any changes in the pharmacokinetics of
acetaminophen. Gleevec pharmacokinetics were not altered in the presence of
single-dose acetaminophen. There is no pharmacokinetic or safety data on the
concomitant use of Gleevec at doses > 400 mg/day or the chronic use of
concomitant acetaminophen and Gleevec.